U.S. Pat. No. 6,875,419 ('419) to Sherry, et al., incorporated herein by reference, describes a class of paramagnetic metal ion based contrast agents which further employ chemical exchange saturation transfer (CEST). The contrast agents described in the '419 patent are derivatives of 1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid (DOTA) wherein each of the four ring nitrogens is substituted by an acetamido containing substituent and contains a chelated metal ion. As described in this patent, images were obtained in solution independent of any targeted component. The images, however, are not sufficiently resolved or sufficiently bright to be useful in a physiological or diagnostic context. This is due to the relatively dilute concentration of the contrast agent.
The method relies on a combination of the paramagnetic relaxation effect of a chelated metal ion to shorten the bulk water relaxation time and the magnetization transfer effected by slowly exchangeable NH or OH in the side chains of a chelating agent after saturating the exchangeable proton using an appropriate radio frequency (RF); hence the term paraCEST. This has the advantage of allowing the image contrast to be switched on or off with a pre-saturation RF pulse, thus avoiding the necessity of obtaining pre-injection and post-injection images. A tutorial review explaining this technique is found in Woods, M., et al., Chem. Soc. Reviews (2006) 35:500-511.
The present applicants have found that a sufficient concentration of contrast agent may be obtained to permit the construction of a useful image if the contrast agent can be concentrated at a target.
It has thus now been found possible to utilize this technique to obtain images of, for example, blood clots by targeting the contrast agent to the location to be imaged. A similar approach with regard to paramagnetic based contrast agents has been described by the present applicants in PCT publication WO 2004/067483 published 12 Aug. 2004.